Thrombospondin Type I Domain Containing 7A 參與血管新生中內皮細胞遷移的功能分析

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研究生：	王捷暉 Wang, Chieh-Huei
論文名稱：	Thrombospondin Type I Domain Containing 7A 參與血管新生中內皮細胞遷移的功能分析 The Functional Analysis of Thrombospondin Type I Domain Containing 7A in Vascular Endothelial Cell Migration during Angiogenesis
指導教授：	莊永仁 Chuang, Yung-Jen
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2011
畢業學年度：	99
語文別：	英文
論文頁數：	84
中文關鍵詞：	血管新生、細胞遷移、斑馬魚、免疫染色
外文關鍵詞：	angiogenesis, cell migration, zebrafish, immunostaining
相關次數：	點閱：2 下載：0
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血管新生是一個高度組織化的過程，包括血管內皮細胞的遷移，複製與分化，並受各類誘導分子調控。近年來，許多參與神經系統發育的分子，亦被發現擁有調控血管內皮細胞遷移的能力，並參與血管新生的過程。本論文研究一新穎蛋白質，Thrombospondin-typeⅠdomain-containing protein 7A (THSD7A)。從實驗結果發現，此新穎蛋白質THSD7A可調控血管內皮細胞的遷移與形成管狀構造的能力，並參與神經與血管交互作用的發育過程。
由基因表現系列分析 (serial analysis of gene expression) 資料庫與組織染色結果中發現，THSD7A高度表現於人類胎盤血管壁組織與臍帶靜脈內皮細胞 (Human Umbilical Vein Endothelial Cell; HUVEC)。為了進一步了解其功能，我在人類臍帶靜脈內皮細胞內改變THSD7A的表現，並觀察此對血管新生的影響。實驗數據顯示，抑制THSD7A可提高HUVEC遷移的能力，並促進其管狀結構的形成。另一方面，當超量表現THSD7A 3’端保守片段於HUVEC中時，可抑制其遷移與形成管狀結構的能力。我們進一步利用免疫染色分析，定位出THSD7A表現分佈於遷移中細胞的最前端，並與細胞骨架分子alpha-V-beta-3 integrin和paxillin共位。而當細胞骨架被破壞時，亦可改變THSD7A於細胞內的分佈。此結果指出，THSD7A可能透過alpha-V-beta-3 integrin和paxillin參與細胞骨架的組織重組，而進一步調控血管內皮細胞的遷移。
為了研究THSD7A在活體內的特性，我們利用全胚胎原位雜交法 (whole mount in-situ hybridization)偵測其於斑馬魚發育過程中的表現時間與位置。不同於人類胎盤血管系統的表現，斑馬魚thsd7a高量表達於發育中的中央神經系統，並沿神經管腹側形成一特殊的表現式樣。此特殊的表現位置正座落於斑馬魚體節血管新生至神經系統的路徑上。利用嗎啉反義核苷酸介導的基因剔除技術抑制Thsd7a的蛋白質表達，可造成遷移中的內皮細胞偏軌，破壞體節血管新生的典型樣式。
綜合本論文數據結果，我們發現THSD7A可透過細胞骨架重組以調控血管內皮細胞的遷移，並於斑馬魚發育中，參與神經與血管的交互作用。本研究結果發表一新穎蛋白質以探討血管新生的分子機轉，並有助於釐清神經與血管交互作用的複雜機制。

Angiogenesis is a highly organized process under the control of guidance cues that direct endothelial cell (EC) migration, proliferation and differentiation. Recently, many molecules that were initially described as regulators of neural guidance were subsequently shown to also direct EC migration during angiogenesis. Here we report a novel protein, Thrombospondin-typeⅠDomain-containing Protein 7A (THSD7A), which is required for EC migration and involved in the vascular patterning during development.
Identified by SAGE (serial analysis of gene expression) database mining and immunohistochemistry, THSD7A is highly expressed in human placenta vasculatures. To determine the function of THSD7A, we altered endogenous THSD7A expression in human umbilical vein endothelial cells (HUVECs) for subsequent angiogenesis assays. Our data indicated that downregulation of THSD7A in HUVECs enhanced cell migration and promoted tube formation, while overexpression of a THSD7A carboxyl-terminal fragment inhibited HUVEC migration and disrupted tube formation. Immunohistological analysis revealed that THSD7A was expressed at the leading edge of migrating HUVECs, and it co-localized with alpha-V-beta-3 integrin and paxillin. This distribution was dispersed from focal adhesions after disruption of the actin cytoskeleton, suggesting the involvement of THSD7A in alpha-V-beta-3 integrin and paxillin that mediates cytoskeletal reorganization during directed EC migration.
To characterize THSD7A in vivo, we performed whole-mount in-situ hybridization to reveal the spatiotemporal expression of THSD7A orthologue during zebrafish embryonic development, by which we detected zebrafish thsd7a transcripts in the central nervous system. Notably, this expression exhibited a unique pattern along the ventral edge of neural tube, correlating with the growth path of angiogenic intersegmental vessels (ISVs). Antisense oligonucleotide-mediated gene knockdown of Thsd7a caused a lateral deviation of angiogenic ECs below the thsd7a-expressing sites, resulting in aberrant ISV patterning.
Collectively, our study revealed that THSD7A mediates angiogenic EC migration via cytoskeletal reorganization, and that zebrafish Thsd7a is a neural protein required for ISV angiogenesis during development. Future analysis on this novel protein shall provide a new perspective on the underlying mechanisms of directed EC migration, and shed light on the complex communication network between the nervous and vascular systems.

Acknowledge    i
Abstract    ii
Abstract in Chinese 中文摘要    iv

Chapter 1/ Introduction    1
1.1 Introduction of angiogenesis    1
1.2 Molecular mechanisms underlying angiogenesis    2
1.3 Developmental angiogenesis of zebrafish intersegmental vessels    4
1.4 Research aims    5

Chapter 2/ Materials and Methods    7
2.1 Ethics Statement    7
2.2 Primary isolation and culture of Human Umbilical Vein Endothelial Cell    7
2.3 Immunostaining    8
2.4 Plasmid construction    8
2.5 Plasmid transfection    9
2.6 shRNA Gene silencing    10
2.7 Migration assay    10
2.8 Tube formation assay    11
2.9 Cloning of zebrafish Thsd7a ortholog    12
2.10 Phylogenetic analysis    12
2.11 Whole-mount in situ hybridization (ISH)    12
2.12 Alkaline phosphatase staining    14
2.13 Morpholino injection and mRNA rescue    14
2.14 Microangiography    15
2.15 Real-time quantification polymerase chain reaction (RT-qPCR)    15
2.16 Statistical analysis    16

Chapter 3    17
Thrombospondin Type I Domain Containing 7A (THSD7A) Mediates Endothelial Cell Migration and Tube Formation    17
3.1 THSD7A was identified as a novel EC-subtype gene    17
3.2 THSD7A inhibited primary endothelial cell migration and tube formation in vitro    18

3.3 THSD7A was expressed in the leading edge of migrating HUVECs and joined the □v□3-paxillin focal complex.    19

Chapter 4    22
Zebrafish Thsd7a is a Neural Protein Required for Angiogenic Patterning during Development    22
4.1 THSD7A is conserved among vertebrates    22
4.2 The thsd7a transcripts were detected in the developing central nervous system in zebrafish and mouse embryos.    23
4.3 Morpholino knockdown of Thsd7a in zebrafish embryos.    24
4.4 Thsd7a is required for ISV angiogenesis during zebrafish development    25
4.5 Knockdown of Thsd7a impairs ISV angiogenic patterning    28

Chapter 5/ Unpublished Data    30
5.1 THSD7A was involved in actin cytoskeletal reorganization in HUVECs.    30
5.2 Other phenotypes in Thsd7a morphants    30

Chapter 6/ Future Works    33

List of Tables
Table 1. Phenotype frequencies of ISV defects in embryos at 30-31 hpf.    37
Table 2. Phenotype frequencies of ISV defects in embryos at 50 hpf.    38
Table 3. Phenotype frequencies of circulation defects in embryos at 50 hpf.    39

List of Figures
Fig. 1. Domain analysis of THSD7A amino acid sequence.    40
Fig. 2. THSD7A transcription is predicted to produce 9 different mRNA variants.    41
Fig. 3. THSD7A protein is expressed in placenta endothelial cells.    42
Fig. 4. Western blot analysis of THSD7A expression in HUVECs.    43
Fig. 5. THSD7A inhibits HUVEC migration and tube formation.    44
Fig. 6. THSD7A expression is down-regulated in HUVECs by shRNA interference.    45

Fig. 7. THSD7A is co-localized with □V□3 integrin and paxillin at the extremities of the cytoskeleton in HUVECs.    46
Fig. 8. THSD7A disperses from focal adhesions upon inhibition of actin polymerization.    47
Fig. 9. Thsd7a is conserved among vertebrates.    49
Fig. 10. thsd7a expression levels increase during embryogenesis.    50
Fig. 11. thsd7a transcripts were detected in the zebrafish developing nervous system.    51
Fig. 12. The mouse Thsd7a ortholog is expressed in the central nervous system at E12.5.    52
Fig. 13. Morpholino knockdown of Thsd7a in zebrafish embryos.    53
Fig. 14. Knockdown of Thsd7a impairs ISV angiogenesis.    54
Fig. 15. Spatial relationship between Thsd7a expression and the ISV pattern.    55
Fig. 16. Knockdown of Thsd7a impairs ISV patterning at 50hpf.    56
Fig. 17. The model for the role of Thsd7a in endothelial cell migration during ISV angiogenesis.    57
Fig. 18. Knockdown of THSD7A in HUVECs induces multiple membrane ruffles.    58
Fig. 19. Knockdown of Thsd7a causes developmental defects of aortic arches at 3 day post-fertilization.    59
Fig. 20. Thsd7a knockdown disrupts vascular development.    60
Fig. 21. Blood circulation follows the ISV structure.    61
Fig. 22. Heart phenotypes in the morphant and the control.    62
Fig. 23. Thsd7a is required for intraspinal motor axon development.    63
Fig. 24. thsd7a expression co-localizes with the neural stem cell pan marker, nestin.    64
Fig. 25. THSD7A transcript was prominently expressed in the human fetal brain.    65
Fig. 26. Model for the role of THSD7A in endothelial cell migration.    66

References    67

Appendix    73

                                

1. Cleaver, O. & Melton, D.A. Endothelial signaling during development. Nat Med 9, 661-668 (2003).
2. Suchting, S., Bicknell, R. & Eichmann, A. Neuronal clues to vascular guidance. Exp Cell Res 312, 668-675 (2006).
3. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6, 273-286 (2007).
4. Carmeliet, P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 6, 389-395 (2000).
5. Djonov, V., Schmid, M., Tschanz, S.A. & Burri, P.H. Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ Res 86, 286-292 (2000).
6. Kubis, N. & Levy, B.I. Understanding angiogenesis: a clue for understanding vascular malformations. J Neuroradiol 31, 365-368 (2004).
7. Djonov, V., Baum, O. & Burri, P.H. Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res 314, 107-117 (2003).
8. Dejana, E., Orsenigo, F. & Lampugnani, M.G. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121, 2115-2122 (2008).
9. Fukumura, D. et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98, 2604-2609 (2001).
10. Sawada, N., Salomone, S., Kim, H.H., Kwiatkowski, D.J. & Liao, J.K. Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1. Circ Res 103, 360-368 (2008).
11. Pepper, M.S. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 21, 1104-1117 (2001).
12. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161-174 (2002).
13. Seandel, M., Noack-Kunnmann, K., Zhu, D., Aimes, R.T. & Quigley, J.P. Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen. Blood 97, 2323-2332 (2001).
14. Xu, J. et al. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivo. J Cell Biol 154, 1069-1079 (2001).
15. Galvez, B.G., Matias-Roman, S., Albar, J.P., Sanchez-Madrid, F. & Arroyo, A.G. Membrane type 1-matrix metalloproteinase is activated during migration of human endothelial cells and modulates endothelial motility and matrix remodeling. J Biol Chem 276, 37491-37500 (2001).
16. Davis, G.E., Koh, W. & Stratman, A.N. Mechanisms controlling human endothelial lumen formation and tube assembly in three-dimensional extracellular matrices. Birth Defects Res C Embryo Today 81, 270-285 (2007).
17. Koh, W., Mahan, R.D. & Davis, G.E. Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J Cell Sci 121, 989-1001 (2008).
18. Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A. & Betsholtz, C. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126, 3047-3055 (1999).
19. Fukuhara, S. et al. Angiopoietin-1/Tie2 receptor signaling in vascular quiescence and angiogenesis. Histol Histopathol 25, 387-396 (2010).
20. Makanya, A.N. et al. Microvascular endowment in the developing chicken embryo lung. Am J Physiol Lung Cell Mol Physiol 292, L1136-1146 (2007).
21. Makanya, A.N., Stauffer, D., Ribatti, D., Burri, P.H. & Djonov, V. Microvascular growth, development, and remodeling in the embryonic avian kidney: the interplay between sprouting and intussusceptive angiogenic mechanisms. Microsc Res Tech 66, 275-288 (2005).
22. Suri, C. et al. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87, 1171-1180 (1996).
23. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511-2514 (1999).
24. Oh, S.J., Kurz, H., Christ, B. & Wilting, J. Platelet-derived growth factor-B induces transformation of fibrocytes into spindle-shaped myofibroblasts in vivo. Histochem Cell Biol 109, 349-357 (1998).
25. Burri, P.H. & Djonov, V. Intussusceptive angiogenesis--the alternative to capillary sprouting. Mol Aspects Med 23, S1-27 (2002).
26. Kawakami, K. Tol2: a versatile gene transfer vector in vertebrates. Genome Biol 8 Suppl 1, S7 (2007).
27. Wienholds, E. & Plasterk, R.H. Target-selected gene inactivation in zebrafish. Methods Cell Biol 77, 69-90 (2004).
28. Meng, X., Noyes, M.B., Zhu, L.J., Lawson, N.D. & Wolfe, S.A. Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases. Nat Biotechnol 26, 695-701 (2008).
29. Doyon, Y. et al. Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases. Nat Biotechnol 26, 702-708 (2008).
30. Childs, S., Chen, J.N., Garrity, D.M. & Fishman, M.C. Patterning of angiogenesis in the zebrafish embryo. Development 129, 973-982 (2002).
31. Isogai, S., Lawson, N.D., Torrealday, S., Horiguchi, M. & Weinstein, B.M. Angiogenic network formation in the developing vertebrate trunk. Development 130, 5281-5290 (2003).
32. Eichmann, A., Makinen, T. & Alitalo, K. Neural guidance molecules regulate vascular remodeling and vessel navigation. Genes Dev 19, 1013-1021 (2005).
33. Baldessari, D. & Mione, M. How to create the vascular tree? (Latest) help from the zebrafish. Pharmacol Ther 118, 206-230 (2008).
34. Carmeliet, P. Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 4, 710-720 (2003).
35. Torres-Vazquez, J. et al. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev Cell 7, 117-123 (2004).
36. Lu, X. et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179-186 (2004).
37. Weinstein, B.M. Vessels and nerves: marching to the same tune. Cell 120, 299-302 (2005).
38. Wang, C.H. et al. Thrombospondin type I domain containing 7A (THSD7A) mediates endothelial cell migration and tube formation. J Cell Physiol 222, 685-694 (2010).
39. Jaffe, E.A., Nachman, R.L., Becker, C.G. & Minick, C.R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52, 2745-2756 (1973).
40. Tamura, K., Dudley, J., Nei, M. & Kumar, S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24, 1596-1599 (2007).
41. Thierry-Mieg, D. & Thierry-Mieg, J. AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 7 Suppl 1, S12 11-14 (2006).
42. Nakayama, M., Kikuno, R. & Ohara, O. Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs. Genome Res 12, 1773-1784 (2002).
43. Lamalice, L., Le Boeuf, F. & Huot, J. Endothelial cell migration during angiogenesis. Circ Res 100, 782-794 (2007).
44. Moissoglu, K. & Schwartz, M.A. Integrin signalling in directed cell migration. Biol Cell 98, 547-555 (2006).
45. Berrier, A.L. & Yamada, K.M. Cell-matrix adhesion. J Cell Physiol 213, 565-573 (2007).
46. Katz, B.Z. et al. Physical state of the extracellular matrix regulates the structure and molecular composition of cell-matrix adhesions. Mol Biol Cell 11, 1047-1060 (2000).
47. Gao, B., Saba, T.M. & Tsan, M.F. Role of alpha(v)beta(3)-integrin in TNF-alpha-induced endothelial cell migration. Am J Physiol Cell Physiol 283, C1196-1205 (2002).
48. Brown, M.C. & Turner, C.E. Paxillin: adapting to change. Physiol Rev 84, 1315-1339 (2004).
49. Hynes, R.O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69, 11-25 (1992).
50. Hodivala-Dilke, K.M., Reynolds, A.R. & Reynolds, L.E. Integrins in angiogenesis: multitalented molecules in a balancing act. Cell Tissue Res 314, 131-144 (2003).
51. Kabir-Salmani, M. et al. Alphavbeta3 integrin signaling pathway is involved in insulin-like growth factor I-stimulated human extravillous trophoblast cell migration. Endocrinology 144, 1620-1630 (2003).
52. West, K.A. et al. The LD4 motif of paxillin regulates cell spreading and motility through an interaction with paxillin kinase linker (PKL). J Cell Biol 154, 161-176 (2001).
53. May, J.A. et al. GPIIb-IIIa antagonists cause rapid disaggregation of platelets pre-treated with cytochalasin D. Evidence that the stability of platelet aggregates depends on normal cytoskeletal assembly. Platelets 9, 227-232 (1998).
54. Zhang, P. et al. Pim-3 is expressed in endothelial cells and promotes vascular tube formation. J Cell Physiol 220, 82-90 (2009).
55. Wang, C.H. et al. Thrombospondin type I domain containing 7A (THSD7A) mediates endothelial cell migration and tube formation. J Cell Physiol 222, 685-694.
56. Kurz, H. Physiology of angiogenesis. J Neurooncol 50, 17-35 (2000).
57. Bedell, V.M. et al. roundabout4 is essential for angiogenesis in vivo. Proc Natl Acad Sci U S A 102, 6373-6378 (2005).
58. Lawson, N.D. & Weinstein, B.M. In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248, 307-318 (2002).
59. Leung, T. et al. Zebrafish G protein gamma2 is required for VEGF signaling during angiogenesis. Blood 108, 160-166 (2006).
60. Heisenberg, C.P. et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature 405, 76-81 (2000).
61. Kantor, D.B. et al. Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44, 961-975 (2004).
62. Hilario, J.D., Rodino-Klapac, L.R., Wang, C. & Beattie, C.E. Semaphorin 5A is a bifunctional axon guidance cue for axial motoneurons in vivo. Dev Biol (2008).
63. Artigiani, S. et al. Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 5, 710-714 (2004).
64. Mahler, J. & Driever, W. Expression of the zebrafish intermediate neurofilament Nestin in the developing nervous system and in neural proliferation zones at postembryonic stages. BMC Dev Biol 7, 89 (2007).
65. Vogelezang, M., Forster, U.B., Han, J., Ginsberg, M.H. & ffrench-Constant, C. Neurite outgrowth on a fibronectin isoform expressed during peripheral nerve regeneration is mediated by the interaction of paxillin with alpha4beta1 integrins. BMC Neurosci 8, 44 (2007).
66. Woo, S. & Gomez, T.M. Rac1 and RhoA promote neurite outgrowth through formation and stabilization of growth cone point contacts. J Neurosci 26, 1418-1428 (2006).
67. Hodivala-Dilke, K. alphavbeta3 integrin and angiogenesis: a moody integrin in a changing environment. Curr Opin Cell Biol 20, 514-519 (2008).
68. Brooks, P.C., Clark, R.A. & Cheresh, D.A. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264, 569-571 (1994).
69. Reynolds, L.E. et al. Enhanced pathological angiogenesis in mice lacking beta3 integrin or beta3 and beta5 integrins. Nat Med 8, 27-34 (2002).
70. Taverna, D., Crowley, D., Connolly, M., Bronson, R.T. & Hynes, R.O. A direct test of potential roles for beta3 and beta5 integrins in growth and metastasis of murine mammary carcinomas. Cancer Res 65, 10324-10329 (2005).
71. Kondo, A. et al. A new paxillin-binding protein, PAG3/Papalpha/KIAA0400, bearing an ADP-ribosylation factor GTPase-activating protein activity, is involved in paxillin recruitment to focal adhesions and cell migration. Mol Biol Cell 11, 1315-1327 (2000).
72. Uchida, H., Kondo, A., Yoshimura, Y., Mazaki, Y. & Sabe, H. PAG3/Papalpha/KIAA0400, a GTPase-activating protein for ADP-ribosylation factor (ARF), regulates ARF6 in Fcgamma receptor-mediated phagocytosis of macrophages. J Exp Med 193, 955-966 (2001).
73. Turner, C.E., West, K.A. & Brown, M.C. Paxillin-ARF GAP signaling and the cytoskeleton. Curr Opin Cell Biol 13, 593-599 (2001).
74. Norman, J.C. et al. ARF1 mediates paxillin recruitment to focal adhesions and potentiates Rho-stimulated stress fiber formation in intact and permeabilized Swiss 3T3 fibroblasts. J Cell Biol 143, 1981-1995 (1998).
75. Boshans, R.L., Szanto, S., van Aelst, L. & D'Souza-Schorey, C. ADP-ribosylation factor 6 regulates actin cytoskeleton remodeling in coordination with Rac1 and RhoA. Mol Cell Biol 20, 3685-3694 (2000).
76. Young, G.D. & Murphy-Ullrich, J.E. The tryptophan-rich motifs of the thrombospondin type 1 repeats bind VLAL motifs in the latent transforming growth factor-beta complex. J Biol Chem 279, 47633-47642 (2004).
77. Ludbrook, S.B., Barry, S.T., Delves, C.J. & Horgan, C.M. The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3. Biochem J 369, 311-318 (2003).
78. Lee, Y.H. et al. Transforming growth factor-beta1 effects on endothelial monolayer permeability involve focal adhesion kinase/Src. Am J Respir Cell Mol Biol 37, 485-493 (2007).
79. Swerlick, R.A., Lee, K.H., Wick, T.M. & Lawley, T.J. Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. J Immunol 148, 78-83 (1992).
80. Siekmann, A.F. & Lawson, N.D. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445, 781-784 (2007).
81. Covassin, L.D., Villefranc, J.A., Kacergis, M.C., Weinstein, B.M. & Lawson, N.D. Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish. Proc Natl Acad Sci U S A 103, 6554-6559 (2006).

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